PubMed · 6853911
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M Warda, A Khan, A Massumi, V Mathur, T Klima, R J Hall. 1983. Radiation-induced valvular dysfunction.. https://doi.org/10.1016/s0735-1097(83)80390-8
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Low-flow states are associated with adverse outcomes in aortic stenosis (AS), but the prognostic value of transvalvular flow rate (TFR) has not been consistently established across studies. This study is a systematic review and meta-analysis of reconstructed time-to-event data was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analyses. PubMed/MEDLINE, EMBASE, and Cochrane Library were searched for studies (published by November 14, 2025) comparing low versus normal TFR in AS. Data were collected from Kaplan-Meier curves. The primary endpoint was all-cause mortality. Survival was assessed using pooled Kaplan-Meier curves, Cox regression, flexible parametric survival models, and restricted mean survival time (RMST) analysis. A total of 9 studies including 6,494 patients were analyzed; 2,575 (39.7%) had low TFR. At 8 years of follow-up, estimated survival was 34.1% (95% confidence interval [CI] 24.7% to 47%) in the low-TFR group and 63% (95% CI 58.9% to 67.4%) in the normal-TFR group. Low TFR was associated with higher all-cause mortality (hazard ratio 1.59, 95% CI 1.45 to 1.74, p < 0.001). We observed a progressively greater hazard over time, with the hazard ratio approaching 1.9 by 8 years. At 8 years, RMST in the normal-TFR group was 7.37 years (95% CI 7.21 to 7.53 years) versus 5.07 years (95% CI 4.91 to 5.23 years) in the low-TFR group, representing a lifetime loss of 2.3 years in the low-TFR group (ΔRMST -2.30 years, 95% CI -2.53 to -2.07 years, p < 0.001). In patients with AS, low TFR is associated with significantly higher mortality and lifetime loss. These findings support TFR as a clinically meaningful marker for risk stratification in AS.
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BACKGROUND: Although family history can be an important risk factor for cardiovascular disease, relatively little is known about the nature of specific genetic risk factors. One approach to this problem is to identify and characterize genes responsible for inherited disorders in the hope that this information will also provide mechanistic insight into common forms of cardiovascular disease. METHODS AND RESULTS: Over the last decade, it has become possible to identify genes that cause human disease by use of the techniques of molecular genetics, specifically genetic linkage analysis, positional cloning, and mutational analyses. We have used these techniques to study three inherited cardiovascular disorders: supravalvular aortic stenosis, Williams syndrome, and long-QT syndrome. We have discovered that the vascular pathology of supravalvular aortic stenosis and Williams syndrome results from mutations involving the elastin gene on chromosome 7q11.23. These mutations include intragenic deletions, translocations, and complete deletion of the elastin gene, suggesting that a quantitative reduction in elastin during vascular development is pathogenically important. To date, only the elastin gene has proved important for supravalvular aortic stenosis. By contrast, genetic linkage analyses in families with long-QT syndrome indicate that at least four distinct genes can cause this disorder. We have identified three LQT loci: LQT1 on chromosome 11p15.5, LQT2 on 7q35-36, and LQT3 on 3p21-24. Recently, we demonstrated that mutations in a putative cardiac potassium channel gene, HERG, are responsible for the chromosome 7-linked form of long-QT syndrome, whereas mutations in the cardiac sodium channel gene SCN5A cause the chromosome 3-linked form of this disorder. HERG mutations and potassium channel biophysics suggest a dominant-negative molecular mechanism and reduced repolarization currents. By contrast, SCN5A mutations probably cause subtle alterations of cardiac sodium channel function and prolonged depolarizing currents. CONCLUSIONS: Molecular genetic analyses of long-QT syndrome, supravalvular aortic stenosis, and Williams syndrome have begun to unravel the mechanisms underlying these inherited disorders. Rapid genetic testing for Williams syndrome is now available using a simple cytogenetic test, fluorescence in situ hybridization, but additional work will be required for long-QT syndrome and autosomal-dominant supravalvular aortic stenosis. Improved diagnosis and mechanistic understanding of these disorders should lead to rational treatment and prevention.